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Flashcards in Receptor Theory Deck (60):
1

What are the 2 principle theories for nerve impulse transmission across the gap at synaptic/neuroeffector junctions?

Electrical
Humoral (chemical)

2

Perfused Frog Heart Experiments

First evidence of chemical transmission
1. The vagus nerve of a frog heart was electrically stimulated, resulting in slowing of the heart
2. The fluid surrounding the heart was pumped to a second frog heart without a vagus nerve
3. The second heart slowed down! (with no electrical stimulation)
This experiment was also repeated with stimulation of the accelerans nerve in heart 1, leading to an increase in the rate of heart 1 and 2

3

What was the conclusion drawn from the 'Perfused Frog Heart Experiments'?

Heart 1 released a chemical substance (vagusstoff/acceleranstoff) from the endings of its vagus/accelerans nerve that was conveyed to the heart 2 in the fluid

4

Vagusstoff

Acetylcholine

5

Acceleranstoff

Noradrenaline

6

Physostigmine

Potentiates acetylcholine by inhibiting cholinesterase

7

Pharmacokinetics

What the body does to the drug

8

Pharmacodynamics

What the drug does to the body, i.e. the relationship between the drug concentration at the site of action and the resulting effect

9

Receptor

A macromolecule with which a drug combines to produce its characteristic effects
A molecular structure on the surface or interior of a cell that binds substances e.g. hormones, neurotransmitters, drugs

10

Example of a ligand-gated ion channel

Nicotinic receptors

11

Examples of GPCRs

Muscarinic receptors, adrenoceptors

12

Example of kinase-linked receptor

Insulin

13

Example of nuclear receptor

Steroid

14

EC50

The concentration of drug that elicits 50 % of the max response
Can only be calculated for AGONISTS

15

pEC50

Negative logarithm of EC50
= pD2

16

Intrinsic efficacy

The capacity of a drug to initiate a response at the receptor

17

Different molecules have...

...different capabilities at inducing a physiological response

18

Antagonist

A drug that binds to a receptor but elicits no response and blocks the responses induced by agonists
i.e. antagonists have affinity for a receptor but no efficacy

19

Partial agonists

Exhibit some agonist activity at a receptor but fail to elicit the full response
Block the responses induced by full agonists as the receptor

20

Alpha

= intrinsic activity
alpha = 1 = full agonist
alpha = 0 = full antagonist
0 < alpha < 1 = partial agonist

21

Affinity

The strength of the interaction between a drug and a receptor, controlled by thermodynamic forces (drug will reside in a pocket of "minimal free energy")

22

The affinity of a drug for a receptor can be modelled by...

... the Langmuir Adsorption Isotherm

23

Langmuir Adsorption Isotherm

The model for affinity

24

Ka

= dissociation constant (K2/K1) => a concentration! The concentration of drug that binds to 50 % of the total receptor population, i.e. p = 0.5 when [A] = Ka

25

Langmuir equation

p = [AR} / [Rt} = [A] / [A] + Ka

26

A smaller Ka value means...

...higher affinity. Higher fraction of receptors are bound. Affinity is the reciprocal of Ka (because Ka is a DISsociation constant, not ASsociation)

27

p =

= fraction of maximal binding.

28

Receptor reserve

The receptors that are not required for a maximal response

29

What is the magnitude of the receptor reserve dependent on?

The agonist's efficacy at the receptor

30

Examples of receptors with constitutive levels of activity

Cannabinoid, dopamine, GABAA (BZ receptors)

31

Two-state model of receptor activation

Agonists have a higher affinity for R* (receptors in their active state)
Inverse agonists have a higher affinity for R (receptors in their inactive resting state)

32

What are the 5 mechanisms of drug antagonism?

Antagonism by receptor block (reversible/irreversible)
Non-competitive antagonism
Chemical antagonism
Pharmacokinetic antagonism
Physiological antagonism

33

Reversible competitive antagonism by receptor block

Leads to parallel shifts in dose-response curves
Increasing agonist concentration will restore receptor occupancy - "surmountable"
Maximal response can still be achieved
Antagonist has a high rate of dissociation and can be displaced by the agonist

34

Irreversible competitive antagonism by receptor block

Leads to decreased maximal response on dose-response curve
Antagonist only dissociates very slowly from the receptor and there is no change in antagonist occupancy when the agonist is applied

35

How might an irreversible competitive antagonist produce a parallel shift in a dose-response curve? i.e. the same effect as a reversible competitive antagonist

For a full agonist with low receptor occupancy (i.e. < 5 %) for maximum response, then > 95 % of receptors must be blocked by the antagonist before the maximal response is reduced
Therefore low concentrations of an irreversible competitive antagonist will only lead to a parallel shift in the dose-response curve

36

Non-competitive antagonism

The antagonist blocks the chain of events after an agonist has bound that lead to the evoked response
e.g. nifedipine = Ca2+ channel blocker, so prevents Ca@+ influx which produces a non-specific block of smooth muscle contraction induced by ACh

37

Chemical antagonism

When two drugs combine in solution so that the effect of the active drug is lost e.g. to counteract overdose of one drug

38

Examples of drugs that are typically irreversible competitive antagonists.

Drugs with reactive groups that can form covalent bonds with the receptor e.g. aspirin

39

Pharmacokinetic antagonism

When one drug reduces the concentration of an active drug at its site of action e.g. through increasing its rate of metabolism/changing rate of absorption/renal excretion

40

Physiological antagonism

The interactions of 2 drugs with opposing actions that cancel each other out, helping to maintain homeostasis

41

Examples of physiological antagonism

Noradrenaline increase blood pressure, ACh decreases blood pressure

42

Dose ratio

The ratio by which the agonist concentration needs to be increased in the presence of a reversible competitive antagonist to elicit the same response

43

Key points of the humoral (chemical) theory

Transmission across the gap is uni-directional ad occurs with a slight delay
Fatigue occurs more readily junctions because transmission is limited by the number of vesicles
Drugs may selectively act at synapses/junctions

44

Total area available for binding

1

45

Area already bound

Theta

46

Area available for binding

1 - theta

47

Alpha (LMI)

Characteristic rate of diffusion of a molecule towards a surface (condensation)

48

V

Characteristic rate of dissociation of a molecule from a surface (evaporation)

49

Mu

Concentration of drug in the medium

50

Rate of adsorption

alpha x mu x (1-theta)

51

Rate of dissociation

Vtheta

52

Theta

(alpha x mu) / [(alpha x mu) + V]

53

Law of Mass Action

The rate of reaction is proportional to the product of the concentrations of the reactants

54

Schild equation

log(DR-1) = log[B] - logKb
When DR = 2, [B] = Kb

55

Kb

= antagonist dissociation constant

56

pA2

= -log[B], where [B] is the concentration of antagonist where twice the concentration of agonist is required to elicit the same response as the agonist alone
= log(DR-1) - log[B]

57

What do similar pA2 values in different tissues indicate?

Identical receptors

58

What does it mean if the slope of a Schild plot = 1?

The antagonist is competitive

59

Write out derivation of the Schild equation

:)

60

Axes on Schild plot

x axis = log[antagonist]
y axis = log(DR-1)